Estradiol plays a critical role in sexual maturation and receptivity. These effects are well characterized: primarily mediated through intracellular estrogen receptors, estradiol initiates changes in gene expression, leading to alterations in cell excitability. But estradiol also influences neuronal plasticity via rapid actions initiated at the plasma membrane. Many intracellular signaling pathways are modulated by estradiol via this unconventional method, influencing various brain functions such as learning and memory, sensorimotor control and nociception. Yet, the mechanism by which estradiol acts at the membrane remains unknown. Preliminary data suggest that estradiol, through interactions with a membrane localized receptor, activates both group I and group II metabotropic glutamate receptors, leading to alterations in several major signaling cascades. This previously undefined mechanism of estradiol action can theoretically account for the majority of unexplained actions of the steroid hormone. The central hypothesis of this proposal is that through activation of metabotropic glutamate receptors, estradiol has profound influences upon brain function. Specific Aim 1 will characterize the effects of estradiol, through activation of metabotropic glutamate receptors, upon CREB and NFATc4, as these two transcription factors are essential regulators of many behaviors. Moreover, we will quantify mRNA expression for genes regulated by CREB and NFATc4 following estradiol administration. Specific Aim 2 will delineate the mechanism by which estradiol activates metabotropic glutamate receptors. Experiments will detail estrogen receptor specificity, gender specific differences in estradiol sensitivity, and interactions between estrogen and glutamate receptors. In sum, this study will attempt to decipher a long standing mystery regarding the actions of estradiol upon the central nervous system. It will potentially provide a unifying theory detailing a principal mechanism by which estradiol can rapidly trigger changes in cell excitability and ultimately lead to a better understanding of how estradiol modulates brain function.